1. Field of the Invention
The present invention relates to ST2L antagonists, polynucleotides encoding the antagonists or fragments thereof, and methods of making and using the foregoing.
2. Description of Related Art
ST2L (IL-1RL1 or IL-33Rα) is a Toll/IL-1 receptor family member expressed on the cell surface of a wide variety of immune cells including T cell, NK/NKT cells, basophils, eosinophils, mast cells and the newly-described non-B/non-T innate lymphoid type 2 cells, nuocytes, and natural helper cells. ST2L expression is also inducible on dendritic cells (DCs), macrophages, and neutrophils. ST2L is able to downregulate the responsiveness of Toll-like Receptors TLR2, TLR4, and TLR9, but also induce type 2 cytokine release via activation by its ligand IL-33 and association with accessory protein IL-1RAcP. IL-33 has been described as an ‘alarmin’, as its full-length form resides in the nuclei of epithelial and endothelial cells during homeostasis, but can be cleaved and released during necrosis.
ST2L signaling requires association of the accessory protein IL-1RAcP to preformed ST2L/IL-33 complex. The accessory protein IL-1RAcP is shared with the IL-1α/β signaling complex. Models of ST2L, IL-33, and IL-1RAcP interactions as well as interactions between IL-1R1 and IL-1RAcP have been proposed (Lingel et al., Cell 17:1398-1410, 2009; Wang et al., Nat Immunol 11:905-11, 2010). Recently, ST2L/IL-33/IL-1RAcP has been shown to form a signaling complex with c-Kit on mast cells, the receptor for stem cell factor (SCF). IL-33 induced cytokine production in primary mast cells in an SCF-dependent manner (Drube et al., Blood 115:3899-906, 2010).
Activation of ST2L leads to excessive type 2 cytokine responses (especially IL-5 and IL-13), mast cell and eosinophil activation, and airway hyper-reactivity, and has also been reported to amplify Th1 and Th17 responses through induction of IFNγ from NKT cells and IL-1β and IL-6 from mast cells. Dysregulation of the ST2L/IL-33 pathway has been implicated in a variety of immune-mediated diseases, including asthma, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, allergic rhinitis, nasal polyposis, and systemic sclerosis (reviewed by Palmer and Gabay, Nat Rev Rheumatol 7:321-9, 2011 and Lloyd, Curr Opin Immunol 22:800-6, 2010; Shimizu et al., Hum Molec Gen 14:2919-27, 2005, Kamekura et al., Clin Exp Allergy 42:218-28, 2012; Manetti et al., Ann Rheum Dis 69:598-605, 2010).
Thus, there is a need for ST2L antagonists that are suitable for use in the treatment of ST2L mediated diseases and disorders.